Summary The lymphatic system performs many crucial functions in health, gathering approximately 4 liters/day of interstitial fluid and returning it to the venous system. As this fluid is filtered, undesirable elements such as tumor cells and foreign pathogens are normally destroyed in lymph nodes. This system is also part of the primary transport mechanism for the immune system. Lymphedema, a debilitating disease for which there is no known cure, affects a large number of cancer patients who have undergone lymph node dissection as well as trauma victims. The lymphatic system is also the major transport route for metastases of the most deadly cancers. Understanding and modeling the transport of lymph remains a challenge. Much of the pumping work comes from the contraction of lymphatic vessel smooth muscle, with valves preventing backflow. We propose to develop a multi-scale network model of the lymphatic circulation based on a combination of physical laws, material descriptions, and models of active cellular processes. Goals of this iterative model development process are to gain a better understanding of normal lymphatic function as well as multiple diseases. PUBLIC HEALTH RELEVANCE: Narrative The lymphatic system is directly involved in Lymhedema, an incurable condition that affects a large percentage of cancer patients who have undergone surgery. It is also involved in the spread of cancer, serving as the principal route of distribution for cancer metastases.